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免疫学的な恒常性の維持に寄与する材料設計

杠, 和樹 YUZURIHA, Kazuki ユズリハ, カズキ 九州大学

2020.05.31

概要

本論文では、抗生物質によるディスバイオーシスと樹状細胞の抗原提示による制御性T細胞の誘導に着目し、免疫学的な恒常性を維持するために必要な材料の設計及び開発の検討を行っている。

免疫学的な恒常性には、腸内細菌叢と免疫細胞のバランスが重要である。腸内細菌叢は、共生するために免疫寛容を誘導しており、我々の免疫システムは正常に保たれている。しかし、抗生物質の投与により免疫寛容性と炎症性の腸内細菌叢のバランスが崩れると、炎症を引き起こすT細胞が誘導されることで、無害な物質においても過剰な免疫応答を引き起こしてしまう。誘導されたT細胞は免疫記憶により、抗原が侵入するたびに活性化されてしまう。そのため、免疫学的な恒常性を改善するためには炎症を抑える制御性T細胞の誘導が必要となる。抗生物質からの腸内細菌叢の保護と制御性T細胞(Treg)の誘導は、免疫学的な恒常性を維持する。

第1章では、免疫学的な恒常性と腸内細菌叢との関係性について要約した。

第2章では、寛容原性表現型を持つ樹状細胞(tDC)とTreg細胞を効果的に誘導するために、DCへのビタミンと抗原ペプチドの共送達を実現するペプチド-ビタミンコンジュゲートを提案する。tDCは、抗原特異的にTregを活性化することにより、アレルギー関連性2型ヘルパーT細胞の活性化を抑制し、アレルギー応答を回避する。効率的にTregの活性化するためには、樹状細胞に免疫調整因子と抗原の共送達する技術が必要となる。そこで著者らは、免疫調節因子であるビタミンと抗原のコンジュゲートを合成するための一般的なスキームの確立を行い、invitroで機能を調査した。ビタミンAとビタミンD3の2種類を使用し、抗原ペプチドのN末端選択的に修飾した。合成した2種類のコンジュゲートの抗炎症性効果を比較し、有意的な効果を示したコンジュゲートを用いてDCを処理した。DCの発現系の変化と抗原提示の評価を評価し、コンジュゲートを取り込んだDCが抗原特異的なTregを誘導する可能性が示された。

第3章では、抗生物質残渣から腸内細菌叢を保護するための抗生物質特異的な吸着剤の開発を試みた。経口投与された抗生物質の残渣は、腸内細菌叢に影響を与える。グラム陽性菌に対して広く使用されているバンコマイシン(VCM)は、ディスバイオーシスを引き起こすとともに、直腸にVCM耐性細菌コロニーを生成する。VCMは、N、N'-ジアセチル-L-Lys-D-Ala-D-Ala-OHなどの細胞壁模倣ペプチドへの結合親和性が比較的高いことが報告されている。そこで著者らは、このペプチドリガンドをペプチド合成用の樹脂に修飾したバンコマイシン特異的な吸着剤の開発を行った。マイクロ粒子(MP)のリガンドの担持量を高めるために、樹状D-リジンのリンカーを介してMPに修飾した。リガンドの担持量に応じて、結合力や最大吸着量は向上したことが示された。また、invivoでのVCMを吸着し、ディスバイオーシスを防いだ。

以上要するに、本論文は、免疫学的な恒常性を維持するための材料開発に向けて、「腸内細菌叢を保護するためのバンコマイシン特異的な吸着剤」と「抗原特異的な免疫寛容を誘導するためのビタミン-ペプチドコンジュゲート」の研究を報告する。これらの知見をもとに、免疫学の恒常性の維持と改善をするための様々な課題を一つずつ検討することで、安全で治療効果の高い方法を実現することが期待される。

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参考文献

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